1. Field of the Invention
The invention is in the fields of organic and medicinal chemistry. In particular, the invention relates to substituted diarylguanidines and analogs and derivatives thereof which are useful for the treatment or prevention of cancer and pain.
2. Related Art
Estimates from the World Health Organization indicated that there are approximately 8.1 million new cases of cancer and 5.2 million cancer deaths each year. In 1998 the American Cancer Society estimates that 1.2 million Americans were diagnosed with cancer and 565,000 people died of the disease and approximately 8 million people are living with a diagnosis of cancer. Even though important strides have been made in cancer detection a number of new agents have been introduced into clinical use the overall 5-year survival for patients with cancer is still only 40% and long-tern survival in the rest of the world is even worse. Most experts agree that little progress has been made in improving the outcome of a cancer patient and achieving a cure continues to be an elusive goal. Cancer is a heterogeneous collection of diseases. Consequently, various treatment strategies do not exhibit equal efficacy in all cancers. When the tumor is small and localized, surgery alone may be sufficient to produce a cure. However, in patients where the tumor may have spread, surgery may provide only limited benefits. In such cases chemotherapy and/or radiation therapy may be used to treat advanced or metastatic disease. However, it is rare that such treatments will produce a cure.
Chemotherapy generally involves the administration of one or more, often, cytotoxic agents. Unlike surgery and radiation that are used for the treatment of local and regional disease, these drugs are distributed systemically and will usually exhibit some degree of efficacy in local, regional, and metastatic disease. Early drugs tended to damage DNA and derived some measure of selectivity by targeting rapidly proliferating populations of cells. Recent advances in cell and molecular biology have allowed pharmaceutical scientists to develop a number of new mechanism-based agents (e.g. taxol, gemcitabine, topotecan, etc.). These drugs potentially offer greater selectivity and reduced toxicity as they attempt to target biochemical or molecular pathways that are inherent to the malignant phenotype. However, most of these drugs are extremely toxic and in many cases the amount of drug that can be delivered is limited by potentially life threatening systemic toxicity. As a result these drugs must often be administered at suboptimal doses thereby limiting their efficacy. In addition, while many cancers will initially respond to one or more drugs, tumor cells often become resistant to a broad spectrum of chemotherapeutic agents leading to disease progression and ultimately death.
Traditionally, cancer has been thought of as a disease of abnormal cell proliferation. This belief has provided the basis for die development of most of the currently used chemotherapeutic agents. Although these drugs are extremely cytotoxic, it was hoped that selectivity could be achieved as a result of the drugs being taken up, to a greater extent, by the rapidly proliferating cancer cells. While this approach has lead to a number of important and clinically active compounds, dose-limiting toxicity continues to be a major problem.
Only recently have we begun to understand that increased cell proliferation is not the only cause of tumor progression and that tumors can develop as a result of decreased cell death. Programmed cell death or apoptosis is a normal process through which damaged or senescent cells are eliminated. Apoptosis is an active and genetically programmed process that is highly regulated requiring gene transcription and the synthesis of specific proteins (Staunton, M. J. and Gaffney, E. F., Arch. Pathol. Lab. Med. 122:310 (1998); Hetts, S. W., J.A.M.A. 279:300 (1998)). Regulation of apoptosis occurs at three levels and involves cell survival or death signals, cell survival or death regulators, and cell death effector.
Exposure to growth promoting factors, such as neuropeptides, causes the cell to progress through the cell cycle. In cases where a cell's DNA becomes damaged, cell cycle arrest occurs until such time that the DNA can be repaired. If the damage cannot be repaired or if the survival factors are withdrawn, the cell receives a signal to undergo apoptosis (Hetts, S. W., J.A.M.A. 279:300 (1998)). However, whether or not a cell undergoes apoptosis is controlled by cell death regulators or through the activation or inactivation of enzymes that function to break down the cells prior to their removal by phagocytosis.
Apoptotic cells exhibit membrane blebbing, nucleus condensation, DNA fragmentation, and changes in mitochondria membrane permeability. At the biochemical and molecular level, caspase, a protease, is activated as a consequence of leakage of Cytochrome C from the mitochondria, and there is an increase in the expression of a number of apoptotic genes, including p53, bax, and gadd.
A variety of neuropeptide receptors have been detected in human cancer cells and in many cases the tumor cells not only respond to but also synthesize and release neuropeptides as part of an autocrine loop (Cuttitta, F., et al., Nature 316:823 (1985)). Moreover, neuropeptides are increasingly implicated in control of cancer cell proliferation (Moody, T. W., et al., Life Sci. 37:105 (1985); Mahmoud, S., et al., Cancer Res. 51:1798 (1991)). Peptides of the substance P, bombesin, gastrin, and cholecystokinin family of peptides initiate a complex cascade of events that promotes cell survival and proliferation (Sethi, T. and Rozengurt, E., Cancer Res. 51:3621 (1991)). Within this context, antagonists with a broad spectrum of activity that interfere with the signal transduction pathways of this family of proteins would be of special interest as they would likely inhibit cell proliferation and induce apoptosis.
The activities of several peptide drugs that antagonize the actions of neuropeptides have previously been described. See, e.g., Hennig, I. M., et al., Int. J. Cancer 61:786 (1995); Layton, J. E., et al., Cancer Res. 48:4783 (1988); Bepler, G., et al., Peptides 9:1367 (1988); Bunn, P. A., Jr., et al., Cancer Res. 54:3602 (1994); Seckl, M. J., et al., Cancer Res. 57:51 (1997); Langdon, S., et al., Cancer Res. 52:4554 (1992); Woll, P. J. and Rozengurt, E., Proc. Natl. Acad. Sci. U.S.A. 85:1859 (1988); Woll, P. J. and Rozengurt, E., Cancer Res. 50:3968 (1990); Jarpe, M. B., et al., J. Biol. Chem. 273:3097 (1998). These agents block neuropeptide-mediated signal transduction and initiate apoptosis in cancer cells while having no effect on normal cells where these peptides are not mitogenic (Jarpe, M. B. et al., J. Biol. Chem. 273:3097 (1998)). While active in vitro, these agents are rapidly degraded, and exhibit poor bioavailability when administered to animals. As a result, these agents tend to exhibit antitumor activity in vivo only when administered in close proximity to the tumor making their use in cancer chemotherapy impractical (Jones, D. A., et al., Peptides 18:1073 (1997); Jones, D. A., et al., Gen. Pharmacol. 28:183 (1997); Davis, T. P., et al., Peptides 13:401 (1992); Halmos, G. and Schally, A. V., Proc. Natl. Acad. Sci. U.S.A. 94:956 (1997)).
Some diarylguanidine derivatives have previously been described and used in a variety of applications, for example:
Dyson, G. M., and Harrington, T., J. Chem. Soc. 191-194 (1940) discloses the synthesis of N-phenyl-N′,N″-di-p-tolyl-guanidine.
Adcock, B., and Lawson, A., J. Chem Soc. 474-479 (1965) discloses the synthesis of N-(2-chloroethyl)-N′,N″-diphenylguanidine.
Jefferson, R., et al., J. Chem. Soc. A, 1584-1590 (1966) discloses the synthesis of some N-dialkyl-N′,N″-di-p-tolyl-guanidine derivatives.
Ram, V. J., et al., Indian J. Pharm. 35:30-32 (1973) discloses the synthesis of some guanidines derived from p-amino, n-butyl and iso-butyl benzoates.
Thomas, E. W., et al., J. Med. Chem. 32:228-236 (1989) discloses the use of some heterocyclic N,N′-di-p-tolyl-guanidine compounds as inhibitors of ADP-induced platelet aggregation.
Singh, T., et al., Lubrication Engineering 46:681-685 (1990) discloses the use of some N-2-benzothiazolyl-N,N′,N″-triarylguanidines as additives for lubricating oil.
Siddiqui, N., et al., Pharmakeftiki 5:120-124 (1992) discloses the synthesis of some N-2-benzothiozolyl-N,N′,N″-triarylguanidine derivatives and the use of these compounds as anticonvulsants.
Fridland, S. V., et al., Zh. Obschch. Khim. 66:791-793 (1996) discloses the synthesis of some N-alkyl-N′,N″-diphenylguanidines.
Ramadas, R., et al., Synlett 9:1053-1054 (1997) discloses the synthesis of some N-alkyl-N′,N″-diphenylguanidines.
U.S. Pat. No. 3,501,557 discloses a process for preparing some 2-aminoethyl-thiophosphate salts.
U.S. Pat. No. 4,281,004 discloses the use of some phenylguanidine derivatives as hypoglycemic agents.
U.S. Pat. No. 4,686,283 discloses some polypeptide analogs of transforming and epidermal growth factor fragments for use as therapeutic and diagnostic agents.
U.S. Pat. No. 5,510,380 discloses some nonpeptide bradykinin antagonists.
U.S. Pat. No. 5,608,106 discloses some salts of pyromellitic acid and their use as epoxy resin curing agents.
European Patent Publication 188333 discloses some guanidine derivatives and their use as anti-inflammatory agents.
Described herein are a series of diarylguanidine compounds that selectively induce apoptosis in cancer. These compounds exhibit significant anticancer activity both in vitro and in vivo providing an alternative approach for treating cancer that may translate into an improvement in long-term survival.